Trisubstituted Imidazoles with a Rigidized Hinge Binding Motif Act As Single Digit nM Inhibitors of Clinically Relevant EGFR L858R/T790M and L858R/T790M/C797S Mutants: An Example of Target Hopping

Abstract

The high genomic instability of non-small cell lung cancer tumors leads to the rapid development of resistance against promising EGFR tyrosine kinase inhibitors (TKIs). A recently detected triple mutation compromises the activity of the gold standard third-generation EGFR inhibitors. We have prepared a set of trisubstituted imidazoles with a rigidized 7-azaindole hinge binding motif as a new structural class of EGFR inhibitors by a target hopping approach from p38α MAPK inhibitor templates. On the basis of an iterative approach of docking, compound preparation, biological testing, and SAR interpretation, robust and flexible synthetic routes were established. As a result, we report two reversible inhibitors 11d and 11e of the clinically challenging triple mutant L858R/T790M/C797S with IC values in the low nanomolar range. Furthermore, we developed a kinome selective irreversible inhibitor 45a with an IC value of 1 nM against the EGFR L858R/T790M double mutant. Target binding kinetics and metabolic stability data are included. These potent mutant EGFR inhibitors may serve as a basis for the development of structurally novel EGFR probes, tools, or candidates.

Patient with Three EGFR Mutations – Gradual Development of Resistance to Previous Targeted Treatment

“…Další cestou je vývoj nových EGFR-TKI. Řada preparátů se nachází v preklinickém vývoji, kdy nové práce poukazují na možné reverzibilní/ ireverzibilní inhibitory cílící na ATP (adenosine triphosphate) vazebné místo pa cientů se třemi mutacemi (původní senzitivní mutace + T790M + C797S) s odliš-nými preparáty zvažovanými pro mutaci L858R a pro deleci na exonu 19 [16][17][18]. Též existuje preklinická práce, která ukazuje na možnou efektivitu brigatinibu (ALK inhibitor, ačkoli původně vyvíjen jako EGFR + ALK inhibitor) spolu s EGFR protilátkou (vedoucí k potřebnému sní-žení EGFR exprese) [12].…”

Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy

“…For this purpose, various molecular scaffolds with different biological effects have been employed. Recently, two equipotent low nM inhibitors 11d and 11e reportedly inhibited the clinically challenging EGFR TM (Juchum et al., ) (Figure ). These inhibitors were synthesized on the base of an off‐target hit of a p38α MAPK‐inhibitor, 11h that had been previously reported by Gunthert et al.…”

“…Activating mutations in the catalytic domain of EGFR is found to be a major oncogenic driver of NSCLC (Chan, Gullick, & Hill, ; Gazdar, Shigematsu, Herz, & Minna, ; Johnson & Jänne, ; Lynch et al., ; Paez et al., ; Pao et al., ; Shigematsu & Gazdar, ). The most prevalent activating mutations, covering more than 90% of mutations, are the L858R point mutation and an exon 19 deletion (Juchum et al., ; Ladanyi & Pao, ). Patients bearing one of these two activating mutations often responded to the first‐generation EGFR tyrosine kinase inhibitors (EGFR‐TKIs), gefitinib (Paez et al., ) and erlotinib (Shepherd et al., ).…”

“…As revealed in a previous study carried out by Juchum and co‐workers, the three inhibitors 11h , 11d, and 11e exhibited 13‐, 36‐, and 33‐fold higher potency, respectively, than the FDA‐approved osimertinib. Although the inhibitory potencies of these compounds were verified in vivo and in vitro (Juchum et al., ), detailed atomistic insights into their therapeutic activities against EGFR TM remain elusive which could further aid the development of novel inhibitors. Here, we provide insights into the structural dynamics and inhibitory activities of 11e , 11h, and 11d against EGFR TM using MD simulation methods and investigated the underlying mechanisms by which changes in the aliphatic chain length from 3 to 2 and 4 led to an improvement in the inhibitory activity of the compound 11h .…”

“…Different postdynamics analysis approaches are used to achieve an overall atomic level understanding from MD simulations. It is, however, important to reiterate that while we seek to provide relevant atomistic insights, this study was designed based on findings obtained from a previous experimental study wherein the differential potencies of the three compounds; 11d , 11e, and 11h were validated in vitro and in vivo (Juchum et al., ).…”